Department of Dermatology, Duke University Medical Center, Durham, North Carolina.
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
J Thorac Oncol. 2021 Mar;16(3):419-427. doi: 10.1016/j.jtho.2020.11.021. Epub 2020 Dec 8.
Identification of patients who can benefit from immune checkpoint blockade (ICB) therapy is key for improved clinical outcome. Recently, U.S. Food and Drug Administration approved tumor mutational burden (TMB) high (TMB-H or TMB ≥ 10) as a biomarker for pembrolizumab treatment of solid tumors. We intend to test the hypothesis that mutations in select genes may be a better predictor of NSCLC response to ICB therapy than TMB-H.
We compiled a list of candidate genes that may predict for benefits from ICB treatment by use of data from a recently published cohort of 350 patients with NSCLC. We then evaluated the influences of different mutation signatures in the candidate genes on ICB efficacy. They were also compared with TMB-H. The predictive powers of different mutation signatures were then evaluated in an independent cohort of patients with NSCLC treated with ICB.
A compound mutation signature, in which two or more of the 52 candidate genes were mutated, accounted for 145 of 350 patients with NSCLC and was associated with considerable ICB treatment benefits. Specifically, the median duration of overall survival was 36 versus 8 months in NSCLC in those with two or more versus none of the 52 genes mutated. Moreover, those patients with the compound mutation signature but had low TMB (<10) achieved significant overall survival benefits when compared with those without the signature but had TMB-H (≥10). Finally, in an independent cohort of 156 patients with ICB-treated NSCLC, the median duration of progression-free survival was 8.3 months versus 3.5 months in those with the compound mutation signature versus those with none mutated in the 52 genes.
A genetic signature with mutations in at least two of 52 candidate genes was superior than TMB-H in predicting clinical benefits for ICB therapy in patients with NSCLC.
鉴定能从免疫检查点阻断（ICB）治疗中获益的患者对于改善临床结局至关重要。最近，美国食品和药物管理局批准肿瘤突变负荷（TMB）高（TMB-H 或 TMB≥10）作为 pembrolizumab 治疗实体瘤的生物标志物。我们旨在检验以下假设，即选择基因的突变可能比 TMB-H 更好地预测非小细胞肺癌（NSCLC）对 ICB 治疗的反应。
我们编制了一份候选基因清单，这些基因的突变可能预示着 NSCLC 患者从 ICB 治疗中获益。然后，我们评估了候选基因中不同突变特征对 ICB 疗效的影响。我们还将其与 TMB-H 进行了比较。然后，在接受 ICB 治疗的 NSCLC 患者的独立队列中评估了不同突变特征的预测能力。
在 350 名 NSCLC 患者中，有 145 名患者存在复合突变特征，即两个或更多的 52 个候选基因发生突变，该特征与相当大的 ICB 治疗获益相关。具体而言，在有两个或更多候选基因发生突变的 NSCLC 患者中，中位总生存期为 36 个月，而在无 52 个基因发生突变的患者中为 8 个月。此外，与无突变特征但 TMB-H（≥10）的患者相比，具有复合突变特征但 TMB<10 的患者具有显著的总生存获益。最后，在接受 ICB 治疗的 NSCLC 患者的 156 名独立队列中，具有复合突变特征的患者中位无进展生存期为 8.3 个月，而无 52 个基因发生突变的患者为 3.5 个月。
在接受 ICB 治疗的 NSCLC 患者中，至少有两个候选基因发生突变的遗传特征在预测 ICB 治疗的临床获益方面优于 TMB-H。
